Unresolved issues in the comparison of therapies and determination of responses in Waldenström macroglobulinemia

Abstract

Waldenstrom macroglobulinemia (WM) is an un- common clinico-pathological syndromic manifesta- tion of lymphoplasmacytic lymphoma. In the more common sub-types of non-Hodgkin lymphoma (NHL) there are internationally accepted robust and reproducible response criteria (1). As with other forms of NHL, WM can lead to tissue infiltration resulting in the clinical, laboratory, and radiological manifestations of lymphadenopathy, hepato-spleno- megaly, and peripheral blood cytopenias. In common with the standard response criteria for NHL, evalua- tion of reduction or complete resolution of these manifestations can be determined using routine clinical evaluation, laboratory, imaging, and bone marrow histologic evaluation criteria. However, WM potentially has two unique addi- tional manifestations which complicate response assessment. First, by definition, all cases of WM are associated with a monoclonal immunoglobulin M (IgM) paraprotein. Extrapolating from observations and conventions derived from studies in multiple myeloma (MM), in WM, while there is modest utility in comparing monoclonal IgM levels across patients as a measure of relative tumor burden, serial measurements of the monoclonal IgM paraprotein level in an individual patient are accepted as a quantitative measure of disease burden. While in MM disease progression can occur in the absence of a paraprotein rise, characterized by an increase of the free light chains in the serum only ('light chain escape'), particularly after a long course of disease with several lines of treatment (2), to our knowledge this has not been reported for WM. In the relatively rare case of WM-transformation to a high-grade lymphoma, this can occur either with or without increasing levels of the pre-existing paraprotein (3). Thus, appropriately quantitative measurement of the serum monoclonal IgM is included in response criteria for WM (4).